Members of the BMP, WNT and HH superfamilies of secreted factors play important roles during embryonic development, and are also critically involved in a variety of human congenital diseases and several types of cancer. In recent years, detailed studies of the signaling pathways triggered by these secreted factors have provided useful information that has been applied to the study, detection and (in some cases), treatment of diseases and degenerative processes in humans. Thus, there is considerable interest in deepening our understanding of the network of interactions that coordinates these signaling pathways, with the hope of identifying new genes involved in human pathologies that may become targets of therapeutic intervention. Here, we propose to use the vertebrate limb bud as a model system to study the mechanisms that coordinate the activities of the BMP, WNT and SHH (Sonic Hedgehog) signaling pathways. Our aim is to further define the roles of these secreted factors (and the signaling pathways they trigger) in the control of cell survival and cell death. We propose to study the role of BMF, WNT and SHH signaling pathways in the control of key aspects of vertebrate limb development, by: 1) Determining the role of the BMP pseudoreceptor BAMIBI in mouse and chick limb buds, specifically in the control of programmed cell death (PCD); 2) Determining the role of the BMP target and WNT antagonist DKK1 in the control of PCD in mouse and chick limb buds; 3) Characterizing the activities of the SHH pathway in the control of programmed cell death (PCD) in the limb; and 4) Isolating and characterizing novel targets of BMP, WNT/B-catenin and SHH signaling in the chick embryo. We will use gain- and loss-of-function strategies to dissect the network of interactions between BMPs, WNTs and HH that operate in mouse and chick limbs. Our proposal takes full advantage of the encyclopedic knowledge accumulated over decades on the molecular and cellular mechanisms that initiate and maintain development of the vertebrate limb bud. Our work has the potential to uncover key regulatory interactions between these signaling pathways, and to define more precisely the involvement of these factors in processes that control both embryonic development and disease initiation and progression.